| |
 |
Prodrugs for liver specific drug delivery |
| 7303739 |
Prodrugs for liver specific drug delivery
|
|
| Patent Drawings: | |
| Inventor: |
Erion, et al. |
| Date Issued: |
December 4, 2007 |
| Application: |
10/844,747 |
| Filed: |
May 12, 2004 |
| Inventors: |
Erion; Mark D. (Del Mar, CA)
Reddy; K. Raja (San Diego, CA)
|
| Assignee: |
Metabasis Therapeutics, Inc. (La Jolla, CA) |
| Primary Examiner: |
Lewis; Patrick |
| Assistant Examiner: |
|
| Attorney Or Agent: |
Sterne, Kessler, Goldstein & Fox P.L.L.C. |
| U.S. Class: |
424/9.1; 424/1.11; 424/1.65; 424/600; 424/601; 424/9.2; 514/7 |
| Field Of Search: |
424/9.1; 424/600; 424/1.11; 424/9.2; 424/1.65; 424/601; 514/7 |
| International Class: |
A61K 49/00; A61K 38/16 |
| U.S Patent Documents: |
3018302; 3796700; 4255566; 4318982; 4340668; 4376165; 4447529; 4952740; 5130303; 5663159; 5962522; 6004927; 6028054; 6312662; 6752981; 6946115; 2005/0288240 |
| Foreign Patent Documents: |
0 481 214; WO 90/08155; WO 90/10636; WO 98/39343; WO 98/39342; WO 98/09668; WO 98/39344; WO 99/45016; WO 00/52015 |
| Other References: |
Bedford et al., "Synthesis of water-soluble prodrugs of the cytotoxic agent combretastatin A4," Bioorganic & Medicinal Chemistry Letters,6(2):157-160 (1996). cited by other.
Bentrude et al., "Stereo- and regiochemistries of the oxidations of 2-methoxy-5-tert-butyl-1,3,2-dioxaphosphorinanes and the cyclic methyl 3', 5'--phosphate of thymidine by H2O/I2 and O2/AIBN to P-chiral phosphates. 170 NMR assignment of phosphorusconfiguration to the diastereomeric thymidine cyclic methyl 3', 5- monophosphates," J. Am. Chem. Soc., 111:3981-3987 (1989). cited by other.
Farquhar et al., "Synthesis and biological evaluation of neutral derivatives of 5-fluoro-2'-deoxyuridine 5'--phosphate," J. Org. Chem., 26:1153 (1983). cited by other.
Farquhar et al., "Biologically-cleavable phosphate protective groups: 4-acyloxy-1,3,2-dioxaphosphorinanes as neutral latent precursors of dianionic phosphates," Tetrahedron Lett., 36:655 (1995). cited by other.
Hayakawa et al., "Benzimidazolium triflate as an efficient promoter for nucleotide synthesis via the phosphoramidite method," J. Org. Chem., 61:7996 (1996). cited by other.
Meier et al., "ADA-bypass by lipophilic cyclo-sal-ddAMP pro-nucleotides. A second example of the efficiency of the cycloSat-concept," Bioorg. Med. Chem. Lett., 7:1577 (1997). cited by other.
Nagamatsu et al., "New phosphorylating agents for general synthesis of mixed phosphate esters," Tetrahedron Lett., 28:2375 (1987). cited by other.
Nakayama et al., "A highly enantioselective synthesis of phosphate triesters," J. Am. Chem. Soc., 112:6936 (1990). cited by other.
Ogg et al., "A reporter gene assay to assess the molecular mechanisms of xenobiotic-dependent induction of the human CYP3A4 gene in vitro," Xenobiotica, 29(3):269-279 (1999). cited by other.
Shih et al., "Studies on potential antitumor agents (III). Synthesis of 4-arylcyclophosphamides," Heterocycles, 9(9):1277-1285 (1978). cited by other.
Wantanabe et al., "Dibenzyl phosphorofluoridate, a new phosphorylating agent," Chem. Pharm. Bull., 38:562 (1990). cited by other.
Yip et al.,-"Use of high-performance liquid chromatography in the preparation of flavin adenine dinucleotide analyte conjugates," J. Chrom., 326:301-310 (1985). cited by other.
Arner, E.S.J. and Eriksson, S., "Mammalian Deoxyribonculeoside Kinases" Pharmac. Ther. 67(2): 155-186, Elsevier Science Ltd. (1995). cited by other.
Bentrude, Wesley G., et al., "Conformations of Saturated Six-Membered-Ring Phosphorus Heterocycles Related to Cyclophosphamide. NMR, X-ray, and Infrared Studies of 2-Methoxy-2-oxo-1,3,2-oxazaphosphorinane and 2-Thio-1,3,2-oxazaphosphorinane," J.Am.Chem Soc. 108:6669-6675, American Chemical Society (1986). cited by other.
Bentrude, Wesley G., et al., "Conformations of Saturated Six-Membered-Ring Phosphorus Heterocycles. 2-Aryl-1,3,2.lamda..sup.5-oxazaphosphorinanes," J. Am.Chem Soc. 110:7119-7127, American Chemical Society (1988). cited by other.
Denmark, Scott E., et al., "Asymmetric Electrophilic Amination of Chiral Phosphorus-Stabilized Anions," Tetrahedron 48/11:2191-2208 Pergamon Press (1992). cited by other.
De Waziers, I., et al., "Cytochrome P450 Isoenzymes, Epoxide Hydrolase and Glutathione Transferases in Rat and Human Hepatic and Extrahepatic Tissues," J. Pharmacol. Exp. Ther. 253:387-394, American Society for Pharmacology and ExperimentalTherapeutics (1990). cited by other.
Elliott, R.L., et al., "Synthesis and Biological Evaluation of Phosphonamidate Peptide Inhibitors of Enkephalinase and Angiotensin-Converting Enzyme," J. Med. Chem. 28:1208-1216, American Chemical Society (1985). cited by other.
Erion, M., et al., "Design, Synthesis, and Characterization of a Series of Cytochrome P.sub.450 3A-Activated Prodrugs (HepDirect Prodrugs) Useful for Targeting Phosph(on)ate-Based Drugs to the Liver," J. Am. Chem. Soc. 126:5154-5163, AmericanChemical Society (Apr. 2004). cited by other.
Erion, M., et al., "Liver-Targeted Drug Delivery Using HepDirect Prodrugs," J. Pharmacol. Exper. Ther. 312:554-560, American Society for Pharmacology and Experimental Therapeutics (Feb. 2005). cited by other.
Erion, M., et al., "HepDirect Prodrugs for Targeting Nucleotide-Based Antiviral Drugs to the Liver," Current Opinion in Investigational Drugs 7/2:109-117, The Thomson Corporation (2006). cited by other.
Freeman, Sally, et al., "Prodrug Design for Phosphates and Phosphonates," Chapter 3 in Progress in Medicinal Chemistry, vol. 34, pp. 111-147, Elsevier Sciences BV (1997). cited by other.
Gorenstein, D.G., et al., "Stereoelectronic Effects in the Reactions of Epimeric 2-Aryloxy-2-oxy-1,3,2-dioxaphosphorinanes and Oxazaphosphorinanes," J. Am. Chem. Soc. 102: 5077-5081, American Chemical Society (1980). cited by other.
Hulst, R., et al., "A New .sup.31P NMR Method for the Enantiomeric Excess Determination of Alcohols, Amines and Amino Acid Esters," Tetrahedron Letters 34(8):1339-1342, Pergamon Press Ltd. (1993). cited by other.
Hunston, R.N., et al., "Synthesis and Biological Properties of Some Cyclic Phosphotriesters Derived from 2'-Deoxy-5-fluorouridine," J. Med Chem. 27:440-444, American Chemical Society (1984). cited by other.
Khamnei, S. and Torrence, P.F., "Neighboring Group Catalysis in the Design of Nucleotide Prodrugs," J. Med. Chem. 39:4109-4115, American Chemical Society (1996). cited by other.
Lorey, M. and Meier, C. "A New Cyclic Phosphoramidate D4T Prodrug Approach CycloAmb-D4T-Phosphoramidates," Nucleosides & Nucleotides 18(4&5):947-948, Marcel Dekker, Inc. (1999). cited by other.
McGuigan, C., et al., "Kinase Bypass: A New Strategy for Anti-HIV Drug Design," Bioorganic & Medicinal Chemistry Letters 3/6:1207-1210, Pergamon Press Ltd. (1993). cited by other.
Meier, C. et al., "Cyclic Saligenyl Phosphotriesters of 2',3'-Dideoxy-2',3'-didehydrothymidine (d4T)--A New Pro-Nucleotide Approach," Bioorganic & Medicinal Chemistry Letters 7/2:99-104, Elsevier Science Ltd. (1997). cited by other.
Merckling, F.A. and Ruedi, P., "Diasteroselectivity in Nucleophilic Displacement Reactions at Phosphorus; Isolation and Characterization of a Pentacoordinated Intermediate," Tetrahedron Letters 37(13): 2217-2220, Elsevier Science Ltd. (1996). citedby other.
Mosbo, J.A., et al., "Dipole Moment, Nuclear Magnetic Resonance, and Infrared Studies of Phosphorus Configurations and Equilibria in 2-R-2-Oxo-1,3,2-dioxaphosphorinanes," J. Org. Chem. 42/9:1549-1555, American Chemical Society (1997). cited by other.
Neidlein, R., et al., "Mild Preparation of 1-Benzyloxyiminoalkylphosphonic Dichlorides: Application to the Synthesis of Cyclic Phosphonic Diesters and Cyclic Monoester Amides," Heterocycles 35/2:1185-1203, Elsevier Science (1993). cited by other.
Nifantyev, E.E., et al., "Synthesis and Structure of Some Stable Phospholane-Phospholanes," Phosphorus, Sulfur and Silicon and Related Elements 113:1-13, Taylor & Francis (1996). cited by other.
Predvoditelev, D.A., et al., "Synthesis of Lipids and Their Models on the Basis of Glycerol Alkylene Phosphites, V. Cyclic Phosophatidylglycerol and Phosphatidylhydroxyhomocholine," J. Org. Chem. USSR, A Translation of Zhur. Org. Khim. 17:1156-1165,Plenum Publishing Corporation (1981). cited by other.
Reddy, K.R., et al., "Stereoselective synthesis of nucleoside monophosphate HepDirect.TM. prodrugs," Tetrahedron Lett. 46:4321-4324, Elsevier Ltd. (2005). cited by other.
Reddy, M.R., et al., "Development of a Quantum Mechanics-Based Free-Energy Perturbation Method: Use in the Calculation of Relative Solvation Free Energies," J. Am. Chem. Soc. 126:6224-6225, American Chemical Society (Apr. 2004). cited by other.
Shan, D., et al., "Prodrug Strategies Based on Intramolecular Cyclization Reactions," J. Pharm. Sci. 86/7:765-767, American Chemical Society and American Pharmaceutical Association (1997). cited by other.
Ten Hoeve, W. and Wynberg, H. "The Design of Resolving Agents, Chiral Cyclic Phosphoric Acids," J. Org. Chem. 50: 4508-4514, American Chemical Society (1985). cited by other. |
|
| Abstract: |
The present invention is directed towards novel cyclic phosph(oramid)ate prodrugs of alcohol-, amine-, and thiol-containing drugs, their preparation, their synthetic intermediates, and their uses. Another aspect of the invention is the use of the prodrugs to treat diseases that benefit from enhanced drug distribution to the liver and like tissues and cells that express cytochrome P450, including hepatitis, cancer, liver fibrosis, malaria, other viral and parasitic infections, and metabolic diseases where the liver is responsible for the overproduction of the biochemical end product, e.g. glucose (diabetes); cholesterol, fatty acids and triglycerides (hyperlipidemia) (atherosclerosis) (obesity). In one aspect, the invention is directed towards the use of the prodrugs to enhance oral drug delivery. In another aspect, the prodrugs are used to prolong pharmacodynamic half-life of the drug. In addition, the prodrug methodology of the current invention is used to achieve sustained delivery of the parent drug. In another aspect, the prodrugs are used to increase the therapeutic index of the drug. In another aspect of the invention, a method of making these prodrugs is described. In another aspect, the prodrugs are also useful in the delivery of diagnostic imaging agents to the liver. |
| Claim: |
We claim:
1. A compound of formula I: ##STR00038## wherein: V, W, and W' are independently selected from the group consisting of --H, alkyl, aralkyl, alicyclic aryl, substituted aryl,heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl; or together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, oraryloxycarbonyloxy attached to a carbon atom that is three atoms from both Y groups attached to the phosphorus; or together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, said cyclic groupis fused to an aryl group at the beta and gamma position to the Y adjacent to V; together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with onesubstituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said additional carbon atoms that is three atoms from a Y attached to the phosphorus; together Z andW are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, and V is aryl, substituted aryl, heteroaryl or substituted heteroaryl; together W and W' are connected via an additional 2-5 atoms to form a cyclicgroup, optionally containing 0-2 heteroatoms, and V is aryl, substituted aryl heteroaryl, or substituted heteroaryl; Z is selected from the group consisting of --CHR.sup.2OH, --CHR.sup.2OC(O)R.sup.3, --CHR.sup.2OC(S)R.sup.3, --CHR.sup.2OC(S)OR.sup.3,--CHR.sup.2OC(O)SR.sup.3, --CHR.sup.2OCO.sub.2R.sup.3, --OR.sup.2, --SR.sup.2, --CHR.sup.2N.sub.3, --CH.sub.2aryl, --CH(aryl)OH, --CH(CH.dbd.CR.sup.2.sub.2)OH, --CH(C.ident.CR.sup.2)OH, --R.sup.2, --NR.sup.2.sub.2, --OCOR.sup.3, --OCO.sub.2R.sup.3,--SCOR.sup.3, --SCO.sub.2R.sup.3, --NHCOR.sup.2, --NHCO.sub.2R.sup.3, --CH.sub.2NHaryl, --(CH.sub.2).sub.p--OR.sup.12, and --(CH.sub.2).sub.p--SR.sup.12; p is an integer 2 or 3; with the provisos that: a) V, Z, W, W' are not all --H; b) when Z is--R.sup.2 or --OR.sup.2, then V is not --H, alkyl aralkyl, or alicyclic; c) when Z is CHR.sup.2OH, then M is not --NH(lower alkyl), --N(lower alkyl).sub.2, --NH(lower alkylhalide), --N(lower alkylhalide).sub.2 or --N(lower alkyl)(lower alkylhalide); and d) when V is aryl or substituted aryl, then M is not --O(D) where D is hydrogen, a metal ion or an ammonium ion; R.sup.2 is selected from the group consisting of R.sup.3 and --H; R.sup.3 is selected from the group consisting of alkyl, aryl,alicyclic, and aralkyl; R.sup.6 is selected from the group consisting of --H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; R.sup.12 is selected from the group consisting of --H, and lower acyl; each Y is independently selectedfrom the group consisting of --O--, and --NR.sup.6--; M is selected from the group of drugs MH containing an --OH, --NHR.sup.2, or --SH group, and that is attached to the phosphorus in formula I via O, N, or S of said OH, --NHR.sup.2, or SH group; andwherein MH is from the class Camptothecins; or a pharmaceutically acceptable prodrugs or salts thereof.
2. The compound of claim 1 wherein MH is selected from the group consisting of Camptothecin, Topotecan, Irinotecan, Lurtotecan, 9-aminocamptothecin, GL-211, DX-8951F, SKF 107874, and SKF 108025.
3. The compound of claim 1 wherein MH is attached to phosphorus via the C-20 hydroxyl group.
4. The compound of claim 1 wherein MH is selected from the group consisting of Camptothecin, Topotecan, Irinotecan, Lurtotecan, and 9-aminocamptothecin.
5. A compound of formula I: ##STR00039## wherein: V, W, and W' are independently selected from the group consisting of --H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl, ortogether V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atomsfrom both Y groups attached to the phosphorus; or together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, said cyclic group is fused to an aryl group at the beta and gamma position to the Yadjacent to V; together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy,alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said additional carbon atoms that is three atoms from a Y attached to the phosphorus; together Z and W are connected via an additional 3-5 atoms to form a cyclic group,optionally containing one heteroatom, and V is aryl, substituted aryl heteroaryl, or substituted heteroaryl; together W and W' are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V is aryl,substituted aryl, heteroaryl, or substituted heteroaryl; Z is selected from the group of --CHR.sup.2OH, --CHR.sup.2OC(O)R.sup.3, --CHR.sup.2OC(S)R.sup.3, --CHR.sup.2OC(S)OR.sup.3, --CHR.sup.2OC(O)SR.sup.3, --CHR.sup.2OCO.sub.2R.sup.3, --OR.sup.2,--SR.sup.2, --CHR.sup.2N.sub.3, --CH.sub.2aryl, --CH(aryl)OH, --CH(CH.dbd.CR.sup.2.sub.2)OH , --CH(C.ident.CR.sup.2)OH, --R.sup.2, --NR.sup.2.sub.2, --OCOR.sup.3, --OCO.sub.2R.sup.3, --SCOR.sup.3, --SCO.sub.2R.sup.3, --NHCOR.sup.2, --NHCO.sub.2R.sup.3,--CH.sub.2NHaryl, --(CH.sub.2).sub.p--OR.sup.12, and --(CH.sub.2).sub.p--SR.sup.12; p is an integer 2 or 3; with the provisos that: a) V, Z, W, W' are not all --H; b) when Z is --R.sup.2 or --OR.sup.2, then V is not --H, alkyl, aralkyl, or alicyclic; c) when Z is CHR.sup.2OH, then M is not --NH(lower alkyl), --N(lower alkyl).sub.2, --NH(lower alkylhalide), --N(lower alkylhalide).sub.2 or --N(lower alkyl)(lower alkylhalide); and d) when V is aryl or substituted aryl then M is not --O(D) where D ishydrogen, a metal ion or an ammonium ion; R.sup.2 is selected from the group consisting of R.sup.3 and --H; R.sup.3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl; R.sup.6 is selected from the group consisting of --H,lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; R.sup.12 is selected from the group consisting of --H, and lower acyl; each Y is independently selected from the group consisting of --O--, and --NR.sup.6--; M is selected from thegroup of drugs MH containing an --OH, --NHR.sup.2, or --SH group, and that is attached to the phosphorus in formula I via O, N, or S of said OH, --NHR.sup.2, or SH group; and wherein MH is selected from the class combretastatin analogues; or apharmaceutically acceptable prodrugs or salts thereof.
6. A compound of formula I: ##STR00040## wherein: V, W, and W' are independently selected from the group consisting of --H, alkyl aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl; ortogether V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atomsfrom both Y groups attached to the phosphorus; or together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, said cyclic group is fused to an aryl group at the beta and gamma position to the Yadjacent to V; together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy,alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said additional carbon atoms that is three atoms from a Y attached to the phosphorus; together Z and W are connected via an additional 3-5 atoms to form a cyclic group,optionally containing one heteroatom, and V is aryl, substituted aryl, heteroaryl, or substituted heteroaryl; together W and W' are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V is aryl,substituted aryl, heteroaryl, or substituted heteroaryl; Z is selected from the group consisting of --CHR.sup.2OH, --CHR.sup.2OC(O)R.sup.3, --CHR.sup.2OC(S)R.sup.3, --CHR.sup.2OC(S)OR.sup.3, --CHR.sup.2OC(O)SR.sup.3, --CHR.sup.2OCO.sub.2R.sup.3,--OR.sup.2, --SR.sup.2, --CHR.sup.2N.sub.3, --CH.sub.2aryl, --CH(aryl)OH, --CH(CH.dbd.CR.sup.2.sub.2)OH, --CH(C.ident.CR.sup.2)OH, --R.sup.2, --NR.sup.2.sub.2, --OCOR.sup.3 , --OCO.sub.2R.sup.3, --SCOR.sup.3, --SCO.sub.2R.sup.3, --NHCOR.sup.2,--NHCO.sub.2R.sup.3, --CH.sub.2NHaryl , --(CH.sub.2).sub.p--OR.sup.12, and --(CH.sub.2).sub.p--SR.sup.12; p is an integer 2 or 3; with the provisos that: a) V, Z, W, W' are not all --H; b) when Z is --R.sup.2 or --OR.sup.2, then V is not --H, alkyl,aralkyl, or alicyclic; c) when Z is CHR.sup.2OH, then M is not --NH(lower alkyl), --N(lower alkyl).sub.2, --NH(lower alkylhalide), --N(lower alkylhalide).sub.2 or --N(lower alkyl)(lower alkylhalide); and d) when V is aryl or substituted aryl, then M isnot --O(D) where D is hydrogen, a metal ion or an ammonium ion; R.sup.2 is selected from the group consisting of R.sup.3and --H; R.sup.3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl; R.sup.6 is selected from the groupconsisting of --H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; R.sup.12 is selected from the group consisting of --H, and lower acyl; each Y is independently selected from the group consisting of --O--, and --NR.sup.6--; M isselected from the group of drugs MH containing an --OH, --NHR.sup.2, or --SH group, and that is attached to the phosphorus in formula I via O, N, or S of said OH, --NHR.sup.2, or SH group; and wherein MH is selected from the class of anthrapyrazoles; or a pharmaceutically acceptable prodrugs or salts thereof.
7. A compound of formula I: ##STR00041## wherein: V, W, and W' are independently selected from the group consisting of --H, alkyl aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl; ortogether V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atomsfrom both Y groups attached to the phosphorus; or together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, said cyclic group is fused to an aryl group at the beta and gamma position to the Yadjacent to V; together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy,alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said additional carbon atoms that is three atoms from a Y attached to the phosphorus; together Z and W are connected via an additional 3-5 atoms to form a cyclic group,optionally containing one heteroatom, and V is aryl, substituted aryl, heteroaryl, or substituted heteroaryl; together W and W' are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V is aryl,substituted aryl, heteroaryl, or substituted heteroaryl; Z is selected from the group consisting of --CHR.sup.2OH, --CHR.sup.2OC(O)R.sup.3, --CHR.sup.2OC(S)R.sup.3, --CHR.sup.2OC(S)OR.sup.3, --CHR.sup.2OC(O)SR.sup.3, --CHR.sup.2OCO.sub.2R.sup.3,--OR.sup.2, --SR.sup.2, --CHR.sup.2N.sub.3, --CH.sub.2aryl, --CH(aryl)OH, --CH(CH.dbd.CR.sup.2.sub.2)OH, --CH(C.ident.CR.sup.2)OH, --R.sup.2, --NR.sup.2.sub.2, --OCOR.sup.3, --OCO.sub.2R.sup.3, --SCOR.sup.3, --SCO.sub.2R.sup.3, --NHCOR.sup.2,--NHCO.sub.2R.sup.3, --CH.sub.2NHaryl, --(CH.sub.2).sub.p--OR.sup.12, and --(CH.sub.2).sub.p--SR.sup.12; p is an integer 2 or 3; with the provisos that: a) V, Z, W, W' are not all --H; b) when Z is --R.sup.2 or --OR.sup.2, then V is not --H, alkyl,aralkyl, or alicyclic; c) when Z is CHR.sup.2OH, then M is not --NH(lower alkyl), --N(lower alkyl).sub.2, --NH(lower alkylhalide), --N(lower alkylhalide).sub.2 or --N(lower alkyl)(lower alkylhalide); and 4) when V is aryl or substituted aryl then M isnot --O(D) where D is hydrogen, a metal ion or an ammonium ion; R.sup.2 is selected from the group consisting of R.sup.3 and --H; R.sup.3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl; R.sup.6 is selected from the groupconsisting of --H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; R.sup.12 is selected from the group consisting of --H, and lower acyl; each Y is independently selected from the group consisting of --O--, and --NR.sup.6--; M isselected from the group of drugs MH containing an --OH, --NHR.sup.2, or --SH group, and that is attached to the phosphorus in formula I via O, N, or S of said OH, --NHR.sup.2, or SH group; and wherein MH is from the class of Anthracyclines; or apharmaceutically acceptable prodrugs or salts thereof.
8. The compound of claim 7 wherein MH is selected from the group consisting of Doxorubicin, Daunorubicin, Idarubicin, Pirarubicin, and Epirubicin.
9. The compound of claim 7 wherein MH is attached to phosphorus via a glycosidic amine.
10. The compound of claim 7 wherein MH is attached to phosphorus via an alcohol or phenolic hydroxy.
11. The compound of claim 10 wherein MH is attached to phosphorus via a glycoside hydroxyl.
12. The compound of claim 8 wherein MH is selected from the group consisting of Pirarubicin and Doxorubicin.
13. The compound of claim 12 wherein MH is attached to phosphorus via a glycosidic amine, an alcohol or a phenolic hydroxyl.
14. A compound of formula I: ##STR00042## wherein: V, W, and W' are independently selected from the group consisting of --H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl; ortogether V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atomsfrom both Y groups attached to the phosphorus; or together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, said cyclic group is fused to an aryl group at the beta and gamma position to the Yadjacent to V; together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy,alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said additional carbon atoms that is three atoms from a Y attached to the phosphorus; together Z and W are connected via an additional 3-5 atoms to form a cyclic group,optionally containing one heteroatom, and V is aryl, substituted aryl, heteroaryl, or substituted heteroaryl; together W and W' are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V is aryl,substituted aryl, heteroaryl, or substituted heteroaryl; Z is selected from the group consisting of --CHR.sup.2OH, --CHR.sup.2OC(O)R.sup.3, --CHR.sup.2OC(S)R.sup.3, --CHR.sup.2OC(S)OR.sup.3, --CHR.sup.2OC(O)SR.sup.3, --CHR.sup.2OCO.sub.2R.sup.3,--OR.sup.2, --SR.sup.2, --CHR.sup.2N.sub.3, --CH.sub.2aryl, --CH(aryl)OH, --CH(CH.dbd.CR.sup.2.sub.2)OH, --CH(C.ident.CR.sup.2)OH, --R.sup.2, --NR.sup.2.sub.2, --OCOR.sup.3, --OCO.sub.2R.sup.3, --SCOR.sup.3, --SCO.sub.2R.sup.3, --NHCOR.sup.2,--NHCO.sub.2R.sup.3, --CH.sub.2NHaryl, --(CH.sub.2).sub.p--OR.sup.12, and --(CH.sub.2).sub.p--SR.sup.12; p is an integer 2 or 3; with the provisos that: a) V, Z, W, W' are not all --H; b) when Z is --R.sup.2 or --OR.sup.2, then V is not --H, alkyl,aralkyl, or alicyclic; c) when Z is CHR.sup.2OH, then M is not --NH(lower alkyl), --N(lower alkyl).sub.2, --NH(lower alkylhalide), --N(lower alkylhalide).sub.2 or --N(lower alkyl)(lower alkylhalide); and d) when V is aryl, or substituted aryl, then Mis not --O(D) where D is hydrogen, a metal ion or an ammonium ion; R.sup.2 is selected from the group consisting of R.sup.3 and --H; R.sup.3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl; R.sup.6 is selected from thegroup consisting of --H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; R.sup.12 is selected from the group consisting of --H, and lower acyl; each Y is independently selected from the group consisting of --O--, and --NR.sup.6--; Mis selected from the group of drugs MH containing an --OH, --NHR.sup.2, or --SH group, and that is attached to the phosphorus in formula I via O, N, or S of said OH, --NHR.sup.2, or SH group; and wherein MH is from the class Enediyne antibiotics; or apharmaceutically acceptable prodrugs or salts thereof.
15. A compound of formula I: ##STR00043## wherein: V, W, and W' are independently selected from the group consisting of --H, alkyl, aralkyl, alicyclic aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl; ortogether V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atomsfrom both Y groups attached to the phosphorus; or together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, said cyclic group is fused to an aryl group at the beta and gamma position to the Yadjacent to V; together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy,alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said additional carbon atoms that is three atoms from a Y attached to the phosphorus; together Z and W are connected via an additional 3-5 atoms to form a cyclic group,optionally containing one heteroatom, and V is aryl, substituted aryl, heteroaryl, or substituted heteroaryl; together W and W' are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V is aryl,substituted aryl, heteroaryl, or substituted heteroaryl; Z is selected from the group consisting of --CHR.sup.2OH , --CHR.sup.2OC(O)R.sup.3, --CHR.sup.2OC(S)R.sup.3, --CHR.sup.2OC(S)OR.sup.3, --CHR.sup.2OC(O)SR.sup.3, --CHR.sup.2OCO.sub.2R.sup.3,--OR.sup.2, --SR.sup.2, --CHR.sup.2N.sub.3, --CH.sub.2aryl, --CH(aryl)OH, --CH(CH.dbd.CR.sup.2.sub.2)OH, --CH(C.ident.CR.sup.2)OH, --R.sup.2, --NR.sup.2.sub.2, --OCOR.sup.3, --OCO.sub.2R.sup.3, --SCOR.sup.3, --SCO.sub.2R.sup.3, --NHCOR.sup.2,--NHCO.sub.2R.sup.3, --CH.sub.2NHaryl, --(CH.sub.2).sub.p--OR.sup.12, and --(CH.sub.2).sub.p--SR.sup.12; p is an integer 2 or 3; with the provisos that: a) V, Z, W, W' are not all --H; b) when Z is --R.sup.2 or --OR.sup.2, then V is not --H, alkyl,aralkyl, or alicyclic; c) when Z is CHR.sup.2OH, then M is not --NH(lower alkyl), --N(lower alkyl).sub.2, --NH(lower alkylhalide), --N(lower alkylhalide).sub.2 or --N(lower alkyl)(lower alkylhalide); and d) when V is aryl or substituted aryl, then M isnot --O(D) where D is hydrogen, a metal ion or an ammonium ion; R.sup.2 is 'selected from the group consisting of R.sup.3 and --H; R.sup.3 is selected from the group consisting of alkyl aryl, alicyclic, and aralkyl; R.sup.6 is selected from the groupconsisting of --H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; R.sup.12 is selected from the group consisting of --H, and lower acyl; each Y is independently selected from the group consisting of --O--, and --NR.sup.6--; M isselected from the group of drugs MH containing an --OH, --NHR.sup.2, or --SH group, and that is attached to the phosphorus in formula I via O, N, or S of said OH, --NHR.sup.2, or SH group; and wherein MH is from the class Taxanes; or a pharmaceuticallyacceptable prodrugs or salts thereof.
16. A compound of formula I: ##STR00044## wherein: W and W' are independently selected from the group consisting of --H, alkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; V is selected from the group consisting of aryl,substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl; Z is selected from the group consisting of --OR.sup.2, --SR.sup.2, --R.sup.2, --NR.sup.2.sub.2, --OCOR.sup.3, --OCO.sub.2R.sup.3, --SCOR.sup.3, --SCO.sub.2R.sup.3,--NHCOR.sup.2, --NHCO.sub.2R.sup.3, --(CH.sub.2).sub.p--OR.sup.12, and --(CH--SR.sup.12; p is an integer 2 or 3; with the provisos that: a) when V is aryl or substituted aryl, then M is not --O(D) where D is hydrogen, a metal ion or an ammonium ion; and b) when Z is CHR.sup.2OH, then M is not --NH(lower alkyl), --N(lower alkyl).sub.2, --NH(lower alkylhalide), --N(lower alkylhalide).sub.2 or --N(lower alkyl)(lower alkylhalide); R.sup.2 is selected from the group consisting of R.sup.3and --H, R.sup.3is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl, R.sup.6 is selected from the group consisting of --H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; R.sup.12 is selected from the group consisting of --H,and lower acyl; each Y is independently selected from the group consisting of --O--, and --NR.sup.6--; M is selected from the group of drugs MH having an --OH, --NHR.sup.2, or --SH group, and that is attached to the phosphorus in formula I via O, N, orS of said OH, --NHR.sup.2, or SH group; and wherein MH is from the class Camptothecins; or a pharmaceutically acceptable prodrugs or salts thereof.
17. The compound of claim 16 wherein MH is selected from the group consisting of Camptothecin, Topotecan, Irinotecan, Lurtotecan, 9-aminocamptothecin, GL-211, DX-8951F, SKF 107874, and SKF 108025.
18. The compound of claim 16 wherein MH is attached to phosphorus via the C-20 hydroxyl group.
19. The compound of claim 16 wherein MH is selected from the group consisting of Camptothecin, Topotecan, Irinotecan, Lurtotecah, and 9-aminocamptothecin.
20. A compound of formula I: ##STR00045## wherein; W and W' are independently selected from the group consisting of --H, alkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; V is selected from the group consisting of aryl,substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl; Z is selected from the group consisting of --OR.sup.2, --SR.sup.2, --R.sup.2, --NR.sup.2.sub.2, --OCOR.sup.3, --OCO.sub.2R.sup.3, --SCOR.sup.3, --SCO.sub.2R.sup.3,--NHCOR.sup.2, --NHCO.sub.2R.sup.3, --(CH.sub.2).sub.p--OR.sup.12, and --(CH.sub.2).sub.p--SR.sup.12; p is an integer 2 or 3; with the provisos that: a) when V is aryl or substituted aryl, then M is not --O(D) where D is hydrogen, a metal ion or anammonium ion; and b) when Z is CHR.sup.2OH, then M is not --NH(lower alkyl), --N(lower alkyl).sub.2, --NH(lower alkylhalide), --N(lower alkylhalide).sub.2 or --N(lower alkyl)(lower alkylhalide); R.sup.2 is selected from the group consisting of R.sup.3and --H; R.sup.3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl; R.sup.6 is selected from the group consisting of --H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; R.sup.12 is selected from the groupconsisting of --H, and lower acyl; each Y is independently selected from the group consisting of --O--, and --NR.sup.6--; M is selected from the group of drugs MH having an --OH, --NHR.sup.2, or --SH group, and that is attached to the phosphorus informula I via O, N, or S of said OH, --NHR.sup.2, or SH group; and wherein MH is selected from the class combretastatin analogues; or a pharmaceutically acceptable prodrugs or salts thereof.
21. A compound of formula I: ##STR00046## wherein: W and W' are independently selected from the group consisting of --H, alkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; V is selected from the group consisting of aryl,substituted aryl, heteroaryl, substituted heteroaryl 1-alkenyl and 1-alkynyl; Z is selected from the group consisting of --OR.sup.2, --SR.sup.2, --R.sup.2, --NR.sup.2.sub.2, --OCOR.sup.3, --OCO.sub.2R.sup.3, --SCOR.sup.3, --SCO.sub.2R.sup.3,--NHCO.sub.2R.sup.2, --NHCO.sub.2R.sup.3, --(CH.sub.2).sub.p--OR.sup.13, and --(CH.sub.2).sub.p--SR.sup.12; p is an integer 2 or 3; with the provisos that: a) when V is aryl or substituted aryl then M is not --O(D) where D is hydrogen, a metal ion oran ammonium ion; and b) when Z is CHR.sup.2OH, then M is not --NH(lower alkyl), --N(lower alkyl).sub.2, --NH(lower alkylhalide), --N(lower alkylhalide).sub.2 or --N(lower alkyl)(lower alkylhalide); R.sup.2 is selected from the group consisting ofR.sup.3 and --H; R.sup.3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl; R.sup.6 is selected from the group consisting of --H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; R.sup.12 is selected fromthe group consisting of --H, and lower acyl; each Y is independently selected from the group consisting of --O--, and --NR.sup.6--; M is selected from the group of drugs MH having an --OH, --NHR.sup.2, or --SH group, and that is attached to thephosphorus in formula I via O, N, or S of said OH, --NHR.sup.2, or SH group; and wherein MH is selected from the class of anthrapyrazoles; or a pharmaceutically acceptable prodrugs or salts thereof.
22. A compound of formula I: ##STR00047## wherein: W and W' are independently selected from the group consisting of --H, alkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; V is selected from the group consisting of aryl,substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl; Z is selected from the group consisting of --OR.sup.2, --SR.sup.2, --R.sup.2, --NR.sup.2.sub.2, --OCOR.sup.3, --OCO.sub.2R.sup.3, --SCOR.sup.3, --SCO.sub.2R.sup.3,--NHCOR.sup.2, --NHCO.sub.2R.sup.3, --(CH.sub.2).sub.p--OR.sup.12, and --(CH.sub.2).sub.p--SR.sup.12; p is an integer 2 or 3; with the provisos that: a) when V is aryl or substituted aryl, then M is not --O(D) where D is hydrogen, a metal ion or anammonium ion; and b) when Z is CHR.sup.2OH, then M is not --NH(lower alkyl), --N(lower alkyl).sub.2, --NH(lower alkylhalide), --N(lower alkylhalide).sub.2 or --N(lower alkyl)(lower alkylhalide); R.sup.2 is selected from the group consisting of R.sup.3and --H; R.sup.3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl; R.sup.6 is selected from the group consisting of --H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; R.sup.12 is selected from the groupconsisting of --H, and lower acyl; each Y is independently selected from the group consisting of --O--, and --NR.sup.6--; M is selected from the group of drugs MH having an --OH, --NHR.sup.2, or --SH group, and that is attached to the phosphorus informula I via O, N, or S of said OH, --NHR.sup.2, or SH group; and wherein MH is from the class of Anthracyclines; or a pharmaceutically acceptable prodrugs or salts thereof.
23. The compound of claim 22 wherein MH is selected from the group consisting of Doxorubicin, Daunorubicin, Idarubicin, Pirarubicin, and Epirubicin.
24. The compound of claim 22 wherein MH is attached to phosphorus via a glycosidic amine.
25. The compound of claim 22 wherein MH is attached to phosphorus via an alcohol or phenolic hydroxy.
26. The compound of claim 22 wherein MH is attached to phosphorus via a glycoside hydroxyl.
27. The compound of claim 23 wherein MH is selected from the group consisting of Pirarubicin and Doxorubicin.
28. The compound of claim 27 wherein MH is attached to phosphorus via a glycosidic amine, an alcohol or a phenolic hydroxyl.
29. A compound of formula I: ##STR00048## wherein: W and W' are independently selected from the group consisting of --H, alkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; V is selected from the group consisting of aryl,substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl; Z is selected from the group consisting of --OR.sup.2, --SR.sup.2, --R.sup.2, --NR.sup.2.sub.2, --OCOR.sup.3, --OCO.sub.2R.sup.3, --SCOR.sup.3, --SCO.sub.2R.sup.3,--NHCOR.sup.2, --NHCO.sub.2R.sup.3, --(CH.sub.2).sub.p--OR.sup.12, and --(CH.sub.2).sub.p--SR.sup.12; p is an integer 2 or 3; with the provisos that: a) when V is aryl or substituted aryl, then M is not --O(D) where D is hydrogen, a metal ion or anammonium ion; and b) when Z is CHR.sup.2OH, then M is not --NH(lower alkyl), --N(lower alkyl).sub.2, --NH(lower alkylhalide), --N(lower alkylhalide).sub.2 or --N(lower alkyl)(lower alkylhalide); R.sup.2 is selected from the group consisting of R.sup.3and --H; R.sup.3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl; R.sup.6 is selected from the group consisting of --H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; R.sup.12 is selected from the groupconsisting of --H, and lower acyl; each Y is independently selected from the group consisting of --O--, and --NR.sup.6--; M is selected from the group of drugs MH having an --OH, --NHR.sup.2, or --SH group, and that is attached to the phosphorus informula I via O, N, or S of said OH, --NHR.sup.2, or SH group; and wherein MH is from the class Enediyne antibiotics; or a pharmaceutically acceptable prodrugs or salts thereof.
30. A compound of formula I: ##STR00049## wherein: W and W' are independently selected from the group consisting of --H, alkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; V is selected from the group consisting of aryl,substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl; Z is selected from the group consisting of --OR.sup.2, --SR.sup.2, --R.sup.2, --NR.sup.2.sub.2, --OCOR.sup.3, --OCO.sub.2R.sup.3, --SCOR.sup.3, --SCO.sub.2R.sup.3,--NHCOR.sup.2, --NHCO.sub.2R.sup.3, --(CH.sub.2).sub.p--OR.sup.12, and --(CH.sub.2).sub.p--SR.sup.12; p is an integer 2 or 3; with the provisos that: a) when V is aryl or substituted aryl, then M is not --O(D) where D is hydrogen, a metal ion or anammonium ion; and b) when Z is CHR.sup.2OH, then M is not --NH(lower alkyl), --N(lower alkyl).sub.2, --NH(lower alkylhalide), --N(lower alkylhalide).sub.2 or --N(lower alkyl)(lower alkylhalide); R.sup.2 is selected from the group consisting ofR.sup.3and --H; R.sup.3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl; R.sup.6 is selected from the group consisting of --H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; R.sup.12 is selected fromthe group consisting of --H, and lower acyl; each Y is independently selected from the group consisting of --O--, and --NR.sup.6--; M is selected from the group of drugs MH having an --OH, --NHR.sup.2, or --SH group, and that is attached to thephosphorus in formula I via O, N, or S of said OH, --NHR.sup.2, or SH group; and wherein MH is from the class Taxanes; or a pharmaceutically acceptable prodrugs or salts thereof.
31. A compound of formula I: ##STR00050## wherein: Z is selected from the group of --CHR.sup.2OH, --CHR.sup.2OC(O)R.sup.3, --CHR.sup.2OC(S)R.sup.3, --CHR.sup.2OCO.sub.2R.sup.3, --CHR.sup.2OC(O)SR.sup.3, --CHR.sup.2OC(S)OR.sup.3, --SR.sup.2,--CH.sub.2aryl, --CH(aryl)OH, --CH(CH.dbd.CR.sup.2.sub.2)OH, --CH(C.ident.CR.sup.2)OH; and --CH.sub.2NHaryl; V, W and W' are independently selected from the group consisting of --H, alkyl, aralkyl, and alicyclic; with the provisos that: a) when Z isCHR.sup.2OH, then M is not --NH(lower alkyl), --N(lower alkyl).sub.2, --NH(lower alkylhalide), --N(lower alkylhalide).sub.2 or --N(lower alkyl)(lower alkylhalide); b) when V is aryl or substituted aryl, then M is not --O(D) where D is hydrogen, a metalion or an ammonium ion; and R.sup.2 is selected from the group consisting of R.sup.3 and --H; R.sup.3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl; R.sup.6 is selected from the group consisting of --H, lower alkyl,acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; each Y is independently selected from the group consisting of --O--, and --NR.sup.6--; M is selected from the group of drugs MH containing an --OH, --NHR.sup.2, or --SH group, and that is attachedto the phosphorus in formula I via O, N, or S of said OH, --NHR.sup.2, or SH group; and wherein MH is from the class Camptothecins; or a pharmaceutically acceptable prodrugs or salts thereof.
32. The compound of claim 31 wherein MH is selected from the group consisting of Camptothecin, Topotecan, Irinotecan, Lurtotecan, 9-aminocamptothecin, GL-211, DX-8951F, SKF 107874, and SKF 108025.
33. The compound of claim 31 wherein MH is attached to phosphorus via the C-20 hydroxyl group.
34. The compound of claim 31 wherein MH is selected from the group consisting of Camptothecin, Topotecan, Irinotecan, Lurtotecan, and 9-aminocamptothecin.
35. A compound of formula I: ##STR00051## wherein: Z is selected from the group of --CHR.sup.2OH, --CHR.sup.2OC(O)R.sup.3, --CHR.sup.2OCO(S)R.sup.3, --CHR.sup.2OCO.sub.2R.sup.3, --CHR.sup.2OC(O)SR.sup.3, --CHR.sup.2OC(S)OR.sup.3, --SR.sup.2,--CH.sub.2aryl, --CH(aryl)OH, --CH(CH.dbd.CR.sup.2.sub.2)OH, --CH(C.ident.CR.sup.2)OH; and --CH.sub.2NHaryl; V, W and W' are independently selected from the group consisting of --H, alkyl, aralkyl, and alicyclic; with the provisos that: a) when Z isCHR.sup.2OH, then M is not --NH(lower alkyl), --N(lower alkyl).sub.2, --NH(lower alkylhalide), --N(lower alkylhalide).sub.2 or --N(lower alkyl)(lower alkylhalide); b) when V is aryl or substituted aryl, then M is not --O(D) where D is hydrogen, a metalion or an ammonium ion; and R.sup.2 is selected from the group consisting of R.sup.3 and --H; R.sup.3 is selected from the group consisting of alkyl aryl, alicyclic, and aralkyl; R.sup.6 is selected from the group consisting of --H, lower alkyl,acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; each Y is independently selected from the group consisting of --O--, and --NR.sup.6--; M is selected from the group of drugs MH containing an --OH, --NHR.sup.2, or --SH group, and that is attachedto the phosphorus in formula I via O, N, or S of said OH, --NHR.sup.2, or SH group; and wherein MH is selected from the class combretastatin analogues; or a pharmaceutically acceptable prodrug or salt thereof.
36. A compound of formula I: ##STR00052## wherein: Z is selected from the group consisting of --CHR.sup.2OH, --CHR.sup.2OC(O)R.sup.3, --CHR.sup.2OC(S)R.sup.3, --CHR.sup.2OCO.sub.2R.sup.3, --CHR.sup.2OC(O)SR.sup.3, --CHR.sup.2OC(S)OR.sup.3,--SR.sup.2, --CH.sub.2aryl, --CH(aryl)OH, --CH(CH.dbd.CR.sup.2.sub.2)OH, --CH(C.ident.CR.sup.2)OH; and --CH.sub.2NHaryl; V, W and W' are independently selected from the group consisting of --H, alkyl, aralkyl, and alicyclic; with the provisos that: a)when Z is CHR.sup.2OH, then M is not --NH(lower alkyl), --N(lower alkyl).sub.2, --NH(lower alkylhalide), --N(lower alkylhalide).sub.2 or --N(lower alkyl)(lower alkylhalide); b) when V is aryl or substituted aryl, then M is not --O(D) where D ishydrogen, a metal ion or an ammonium ion; and R.sup.2 is selected from the group consisting of R.sup.3 and --H; R.sup.3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl; R.sup.6 is selected from the group consisting of --H,lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; each Y is independently selected from the group consisting of --O--, and --NR.sup.6--; M is selected from the group of drugs MH containing an --OH, --NHR.sup.2, or --SH group, and thatis attached to the phosphorus in formula I via O, N, or S of said OH, --NHR.sup.2, or SH group; and wherein MH is selected from the class of anthrapyrazoles; or a pharmaceutically acceptable prodrugs or salts thereof.
37. A compound of formula I: ##STR00053## wherein: Z is selected from the group consisting of --CHR.sup.2OH, --CHR.sup.2OC(O)R.sup.3, --CHR.sup.2OC(S)R.sup.3, --CHR.sup.2OCO.sub.2R.sup.3, --CHR.sup.2OC(O)SR.sup.3, --CHR.sup.2OC(S)OR.sup.3,--SR.sup.2, --CH.sub.2aryl, --CH(aryl)OH, --CH(CH.dbd.CR.sup.2.sub.2)OH, --CH(C.ident.CR.sup.2)OH; and --CH.sub.2NHaryl; V, W and W' are independently selected from the group consisting of --H, alkyl, aralkyl, and alicyclic; with the provisos that: a)when Z is CHR.sup.2OH, then M is not --NH(lower alkyl), --N(lower alkyl).sub.2, --NH(lower alkylhalide), --N(lower alkylhalide).sub.2 or --N(lower alkyl)(lower alkylhalide); b) when V is aryl or substituted aryl, then M is not --O(D) where D ishydrogen, a metal ion or an ammonium ion, and R.sup.2 is selected from the group consisting of R.sup.3 and --H; R.sup.3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl; R.sup.6 is selected from the group consisting of --H,lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; each Y is independently selected from the group consisting of --O--, and --NR.sup.6--; M is selected from the group of drugs MH containing an --OH, --NHR.sup.2, or --SH group, and thatis attached to the phosphorus in formula I via O, N, or S of said OH, --NHR.sup.2, or SH group; and wherein MH is from the class of Anthracyclines; or a pharmaceutically acceptable prodrugs or salts thereof.
38. The compound of claim 37 wherein MH is selected from the group consisting of Doxorubicin, Daunorubicin, Idarubicin, Pirarubicin, and Epirubicin.
39. The compound of claim 37 wherein MH is attached to phosphorus via a glycosidic amine.
40. The compound of claim 37 wherein MH is attached to phosphorus via an alcohol or phenolic hydroxy.
41. The compound of claim 37 wherein MH is attached to phosphorus via a glycoside hydroxyl.
42. The compound of claim 38 wherein MH is selected from the group consisting of Pirarubicin and Doxorubicin.
43. The compound of claim 42 wherein MH is attached to phosphorus via a glycosidic amine, an alcohol or a phenolic hydroxyl.
44. A compound of formula I: ##STR00054## wherein: Z is selected from the group consisting of --CHR.sup.2OH, --CHR.sup.2OC(O)R.sup.3, --CHR.sup.2OC(S)R.sup.3, --CHR.sup.2OCO.sub.2R.sup.3, --CHR.sup.2OC(O)SR.sup.3, --CHR.sup.2OC(S)OR.sup.3,--SR.sup.2, --CH.sub.2aryl , --CH(aryl)OH , --CH(CH.dbd.CR.sup.2.sub.2)OH, --CH(C.ident.CR.sup.2)OH; and --CH.sub.2NHaryl; V, W and W' are independently selected from the group consisting of --H, alkyl, aralkyl, and alicyclic; with the provisos that:a) when Z is CHR.sup.2OH, then M is not --NH(lower alkyl), --N(lower alkyl).sub.2, --NH(lower alkylhalide), --N(lower alkylhalide).sub.2 or --N(lower alkyl)(lower alkylhalide); b) when V is aryl or substituted aryl, then M is not --O(D) where D ishydrogen, a metal ion or an ammonium ion; and R.sup.2 is selected from the group consisting of R.sup.3 and --H; R.sup.3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl; R.sup.6 is selected from the group consisting of --H,lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; each Y is independently selected from the group consisting of --O--, and --NR.sup.6--; M is selected from the group of drugs MH containing an --OH, --NHR.sup.2, or --SH group, and thatis attached to the phosphorus in formula I via O, N, or S of said OH, --NHR.sup.2, or SH group; and wherein MH is from the class Enediyne antibiotics; or a pharmaceutically acceptable prodrugs or salts thereof.
45. A compound of formula I: ##STR00055## wherein: Z is selected from the group of --CHR.sup.2OH, --CHR.sup.2OC(O)R.sup.3, --CHR.sup.2OC(S)R.sup.3, --CHR.sup.2OCO.sub.2R.sup.3, --CHR.sup.2OC(O)SR.sup.3, --CHR.sup.2OC(S)OR.sup.3, --SR.sup.2,--CH.sub.2aryl, --CH(aryl)OH, --CH(CH.dbd.CR.sup.2.sub.2)OH, --CH(C.ident.CR.sup.2)OH; and --CH.sub.2NHaryl; V, W and W' are independently selected from the group consisting of --H, alkyl, aralkyl, and alicyclic; with the provisos that: a) when Z isCHR.sup.2OH, then M is not --NH(lower alkyl), --N(lower alkyl).sub.2, --NH(lower alkylhalide), --N(lower alkylhalide).sub.2 or --N(lower alkyl)(lower alkylhalide); b) when V is aryl or substituted aryl, then M is not --O(D) where D is hydrogen, a metalion or an ammonium ion; and R.sup.2 is selected from the group consisting of R.sup.3 and --H; R.sup.3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl; R.sup.6 is selected from the group consisting of --H, lower alkyl,acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; each Y is independently selected from the group consisting of --O--, and --NR.sup.6--; M is selected from the group of drugs MH containing an --OH, --NHR.sup.2, or --SH group, and that is attachedto the phosphorus in formula I via O, N, or S of said OH, --NHR.sup.2, or SH group; and wherein MH is from the class Taxanes; or a pharmaceutically acceptable prodrugs or salts thereof.
46. A compound of formula VIII: ##STR00056## wherein: Z' is selected from the group consisting of --OH, --OC(O)R.sup.3, --OCO.sub.2R.sup.3, and --OC(O)SR.sup.3; D.sup.3 and D.sup.4 are independently selected from the group consisting of --H,alkyl, --OH, and --OC(O)R.sup.3; R.sup.2 is selected from the group consisting of R.sup.3 and --H; R.sup.3 is selected from the group of alkyl, aryl, alicyclic, and aralkyl; each Y is independently selected from the group of --O--, and --NR.sup.6--; M is selected from the group of drugs MH containing an --OH, --NHR.sup.2, or --SH group, and that is attached to the phosphorus in formula I via O, N, or S of said OH, --NHR.sup.2, or SH group; or a pharmaceutically acceptable prodrugs or salts thereof.
47. The compound of claim 46 wherein MH is selected from the group consisting of antiviral, anticancer, antihyperlipidemic, anti-inflammatory, antifibrotic, anti-diabetic and antiparasitic agents, with the proviso that said anti-diabetic agentis not an FBPase inhibitor.
48. The compound of claim 47 wherein MH is selected from the group consisting of etoposide, teniposide, NK-611, GL-331, camptothecin, irinotecan, 9-aminocamptothecin, GG 211, topotecan, lurtotecan, DX-8951F, SKF 107874, SKF 108025, docetaxel,FCE-28161, paclitaxel, mitoxantrone, combretastatin A-4, Azatoxin, mycophenolic acid, coformycin, deoxycoformycin, S,S-dioxolane Combretastatin A-4, doxorubicin, daunorubicin, idarubicin, epirubicin, pirarubicin, mitomycin, eflornithine, piroxantrone,mitoxantrone, neocarzinostatin, esperamicin, calicheamicin theta, and losoxantrone.
49. The compound of claim 48 wherein MH is selected from the group consisting of etoposide, teniposide, doxorubicin, pirarubicin, mitoxantrone, topotecan, irinotecan, combretastatin A-4, S,S-dioxolane combretastatin, neocarzinostatin, andcalicheamicin.
50. The compound of claim 46 wherein at least one Y group is --O--.
51. The compound of claim 46 wherein both Y groups are --O--.
52. The compound of claim 46 wherein M is attached to phosphorus via an oxygen or nitrogen atom.
53. The compound of claim 46 wherein MH is from the class epipodophyllotoxins.
54. The compound of claim 53 wherein MH is selected from the group consisting of Etoposide, Teniposide, NK-611, GL-331, and Azatoxin.
55. The compound of claim 46 wherein MH is from the class Camptothecins.
56. The compound of claim 55 wherein MH is selected from the group consisting of Camptothecin, Topotecan, Irinotecan, Lurtotecan, 9-aminocamptothecin, GL-211, DX-8951F, SKF 107874, and SKF 108025.
57. The compound of claim 55 wherein MH is attached to phosphorus via the C-20 hydroxyl group.
58. The compound of claim 55 wherein MH is selected from the group consisting of Camptothecin, Topotecan, Irinotecan, Lurtotecan, and 9-aminocamptothecin.
59. The compound of claim 46 wherein MH is selected from the class combretastatin analogues.
60. The compound of claim 46 wherein MH is selected from the class of anthrapyrazoles.
61. The compound of claim 46 wherein MH is from the class of Anthracyclines.
62. The compound of claim 61 wherein MH is selected from the group consisting of Doxorubicin, Daunorubicin, Idarubicin, Pirarubicin, and Epirubicin.
63. The compound of claim 61 wherein MH is attached to phosphorus via a glycosidic amine.
64. The compound of claim 61 wherein MH is attached to phosphorus via an alcohol or phenolic hydroxy.
65. The compound of claim 61 wherein MH is attached to phosphorus via a glycoside hydroxyl.
66. The compound of claim 62 wherein MH is selected from the group consisting of Pirarubicin and Doxorubicin.
67. The compound of claim 66 wherein MH is attached to phosphorus via a glycosidic amine, an alcohol or a phenolic hydroxyl.
68. The compound of claim 46 wherein MR is from the class Enediyne antibiotics.
69. The compound of claim 46 wherein MH is from the class Taxanes.
70. The compound of claim 1, wherein said compound is the compound of Formula I or the pharmaceutically acceptable salt thereof.
71. The compound of claim 5, wherein said compound is the compound of Formula I or the pharmaceutically acceptable salt thereof.
72. The compound of claim 6, wherein said compound is the compound of Formula I or the pharmaceutically acceptable salt thereof.
73. The compound of claim 7, wherein said compound is the compound of Formula I or the pharmaceutically acceptable salt thereof.
74. The compound of claim 14, wherein said compound is the compound of Formula I or the pharmaceutically acceptable salt thereof.
75. The compound of claim 15, wherein said compound is the compound of Formula I or the pharmaceutically acceptable salt thereof.
76. The compound of claim 16, wherein said compound is the compound of Formula I or the pharmaceutically acceptable salt thereof.
77. The compound of claim 20, wherein said compound is the compound of Formula I or the pharmaceutically acceptable salt thereof.
78. The compound of claim 21, wherein said compound is the compound of Formula I or the pharmaceutically acceptable salt thereof.
79. The compound of claim 22, wherein said compound is the compound of Formula I or the pharmaceutically acceptable salt thereof.
80. The compound of claim 29, wherein said compound is the compound of Formula I or the pharmaceutically acceptable salt thereof.
81. The compound of claim 30, wherein said compound is the compound of Formula I or the pharmaceutically acceptable salt thereof.
82. The compound of claim 31, wherein said compound is the compound of Formula I or the pharmaceutically acceptable salt thereof.
83. The compound of claim 35, wherein said compound is the compound of Formula I or the pharmaceutically acceptable salt thereof.
84. The compound of claim 36, wherein said compound is the compound of Formula I or the pharmaceutically acceptable salt thereof.
85. The compound of claim 37, wherein said compound is the compound of Formula I or the pharmaceutically acceptable salt thereof.
86. The compound of claim 44, wherein said compound is the compound of Formula I or the pharmaceutically acceptable salt thereof.
87. The compound of claim 45, wherein said compound is the compound of Formula I or the pharmaceutically acceptable salt thereof.
88. The compound of claim 46, wherein said compound is the compound of Formula VIII or the pharmaceutically acceptable salt thereof. |
| Description: |
|
|
|
|
